*2.7.3.2 Multispot laser*

This technique allows the delivery of laser shots in a much shorter time and in a semi-automatic manner. These are much finer and at a lower intensity, threshold or subthreshold, causing lesser heat and consequently inflammation in the pigmented retinal epithelium. Clinical studies have shown that the effectiveness of the method is similar to classical laser, but fewer complications are encountered regarding retinal scarring and the impact on the visual field.

#### *2.7.3.3 Laser photocoagulation in diabetic macular edema (DME)*

In the case of exudative non-central DME, laser treatment may be considered as an alternative or in combination with intravitreal injections with anti-VEGF. In this case, the laser spots are finer, with a size of 50-100 μm, and lower energy. Laser treatment is inefficient in the case of ischemic macular edema, and so fluorangiography is necessary before therapeutic planning. In the early treatment diabetic retinopathy study (ETDRS) study, when comparing laser photocoagulation with no treatment, there was a decrease in DME from 24% to 12% after 3 years follow-up, while visual acuity improved in only 3% of patients [76].

#### *2.7.4 Intravitreal anti-VEGF*

Clinical and experimental studies have revealed increased VEGF concentration in ocular samples early in the evolution of DR, documenting its role both in increased vascular permeability and in vascular proliferation. Hence, anti-VEGF agents were used first in the treatment of DME and later in PDR management [77] (**Table 3**).

Clinical studies showed that Pegaptanib is the least effective in preventing neovascularization. Comparative studies between bevacizumab, ranibizumab and aflibercept found that they are all effective to decrease DME. However, aflibercept is most powerful in subjects with worse visual acuity [77, 78]. Still, the effect of intravitreal anti- VEGF is temporary and intravitreal therapy should be repeated according to clinical outcome.

#### *2.7.5 Intravitreal steroids*

In cases of DME resistant to anti-VEGF therapy after 3 monthly injections, intravitreal triamcinolone injection or fluocinolone are a therapeutic alternative to reduce DME and improve vision [79]. Their main untoward effects are cataract and transient increase of intraocular pressure.

**263**

*Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)…*

RNA aptamer that binds to the heparin binding site of the VEGF-A165 isomer

Full-length recombinant humanized anti-VEGF monoclonal antibody

Recombinant fragment of the humanized anti-VEGF monoclonal antibody; increased binding affinity for

Recombinant fusion protein of the binding domains of human VEGF-R1 and VEGF-R2, fused with the Fc domain of human IgG1 bind VEGF with greater affinity compared to other anti VEGF and prevent activation of VEGF-R

all VEGF isoforms

**Description of the molecule FDA approval Dose**

For wet age related macular degeneration only

No; "off-label" use 1.25 to 2.5 mg

Yes 0.3 or 0.5 mg in

Yes 2mg/0.05mL

0.3 mg /0.09ml

(0.05-0.1ml)

0.05 mL

Vitreoretinal surgery is crucial in managing advanced DR, in order to mitigate

The main risk factors of DFUs include DM duration and high HbA1c [82–88]. The EURO-Diab group has identified hypertension, smoking and lipid disorders (hypertriglyceridemia, hypercholesterolemia) as additional risk factors [82, 83]. In Western countries, the male sex appears to be more commonly affected, with a risk ratio of 1.6. The co-existence of other microvascular complications (DR, nephropa-

Precipitating trauma is important. However, history of trauma is only identified in 48% of patients with DFUs. By contrast, foot injury without an apparent cause usually results from repeated minor injuries by inappropriate footwear [88–90].

visual loss. Its main indications include vitreous hemorrhage interfering with photocoagulation, tractional and combined tractional and rhegmatogenous retinal detachment, dense premacular hemorrhage and DME with with vitreo-macular traction [80]. The objectives of surgical removal of the vitreous (vitrectomy) include removal of vitreous opacity (usually blood) and/or fibrovascular proliferation, relieving retinal traction, achieving retinal reattachment, and allowing completion of scatter laser photocoagulation. A large case series showed that sight threatening complications are rare and in approximately 90% of cases, vision is improved or stabilized [81]. Vitrectomy may also be beneficial for maculopathy

when traction from the vitreous gel contributes to fluid accumulation.

*DOI: http://dx.doi.org/10.5772/intechopen.96548*

**Pegaptanib**

**Bevacizumab**

**Ranibizumab** (Lucentis; Genentech, San Francisco, CA, USA/ Novartis Ophthalmics, Basel, Switzerland)

**Aflibercept** (Eylea; Regeneron, Tarrytown,

NY, USA)

**Table 3.**

(Macugen; Eyetech Inc, Cedar Knolls, NJ, USA)

(Avastin; Genentech, San Francisco, CA, USA)

*2.7.6 Surgical management of DR*

*Anti VEGF agents used in DME treatment.*

**3. Diabetic foot ulcers (DFUs)**

thy) increases the risk of DFUs.

**3.1 Risk factors**

**Description of the molecule FDA approval Dose Pegaptanib** (Macugen; Eyetech Inc, Cedar Knolls, NJ, USA) RNA aptamer that binds to the heparin binding site of the VEGF-A165 isomer For wet age related macular degeneration only 0.3 mg /0.09ml **Bevacizumab** (Avastin; Genentech, San Francisco, CA, USA) Full-length recombinant humanized anti-VEGF monoclonal antibody No; "off-label" use 1.25 to 2.5 mg (0.05-0.1ml) **Ranibizumab** (Lucentis; Genentech, San Francisco, CA, USA/ Novartis Ophthalmics, Basel, Switzerland) Recombinant fragment of the humanized anti-VEGF monoclonal antibody; increased binding affinity for all VEGF isoforms Yes 0.3 or 0.5 mg in 0.05 mL **Aflibercept** (Eylea; Regeneron, Tarrytown, NY, USA) Recombinant fusion protein of the binding domains of human VEGF-R1 and VEGF-R2, fused with the Fc domain of human IgG1 bind VEGF with greater affinity compared to other anti VEGF and prevent activation of VEGF-R Yes 2mg/0.05mL

*Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)… DOI: http://dx.doi.org/10.5772/intechopen.96548*

#### **Table 3.**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

retinal scarring and the impact on the visual field.

*2.7.3.3 Laser photocoagulation in diabetic macular edema (DME)*

while visual acuity improved in only 3% of patients [76].

hemorrhage [73–75].

*2.7.3.2 Multispot laser*

*2.7.4 Intravitreal anti-VEGF*

according to clinical outcome.

transient increase of intraocular pressure.

*2.7.5 Intravitreal steroids*

[77] (**Table 3**).

the VEGF-secreting ischemic retina. Immediate complications are related to eye discomfort (tingling sensation/low-intensity pain) and mild ocular inflammation (caused by retinal burns). For this reason, it is recommended to space the laser photocoagulation in 3-4 sessions. In the long run, potential complications include hemeralopia, "fan shaped" visual field changes, or even concentric narrowing of the visual field through widening of scars and subretinal fibrosis. Other less frequent side effects are membrane injury, with secondary choroidal neovascularization, damage of ciliary nerves with permanently mydriasis and loss of accommodation, uveal effusion, angle closure glaucoma, serous retinal detachment, and vitreous

This technique allows the delivery of laser shots in a much shorter time and in a semi-automatic manner. These are much finer and at a lower intensity, threshold or subthreshold, causing lesser heat and consequently inflammation in the pigmented retinal epithelium. Clinical studies have shown that the effectiveness of the method is similar to classical laser, but fewer complications are encountered regarding

In the case of exudative non-central DME, laser treatment may be considered as an alternative or in combination with intravitreal injections with anti-VEGF. In this case, the laser spots are finer, with a size of 50-100 μm, and lower energy. Laser treatment is inefficient in the case of ischemic macular edema, and so fluorangiography is necessary before therapeutic planning. In the early treatment diabetic retinopathy study (ETDRS) study, when comparing laser photocoagulation with no treatment, there was a decrease in DME from 24% to 12% after 3 years follow-up,

Clinical and experimental studies have revealed increased VEGF concentration in ocular samples early in the evolution of DR, documenting its role both in increased vascular permeability and in vascular proliferation. Hence, anti-VEGF agents were used first in the treatment of DME and later in PDR management

Clinical studies showed that Pegaptanib is the least effective in preventing neovascularization. Comparative studies between bevacizumab, ranibizumab and aflibercept found that they are all effective to decrease DME. However, aflibercept is most powerful in subjects with worse visual acuity [77, 78]. Still, the effect of intravitreal anti- VEGF is temporary and intravitreal therapy should be repeated

In cases of DME resistant to anti-VEGF therapy after 3 monthly injections, intravitreal triamcinolone injection or fluocinolone are a therapeutic alternative to reduce DME and improve vision [79]. Their main untoward effects are cataract and

**262**

*Anti VEGF agents used in DME treatment.*

#### *2.7.6 Surgical management of DR*

Vitreoretinal surgery is crucial in managing advanced DR, in order to mitigate visual loss. Its main indications include vitreous hemorrhage interfering with photocoagulation, tractional and combined tractional and rhegmatogenous retinal detachment, dense premacular hemorrhage and DME with with vitreo-macular traction [80]. The objectives of surgical removal of the vitreous (vitrectomy) include removal of vitreous opacity (usually blood) and/or fibrovascular proliferation, relieving retinal traction, achieving retinal reattachment, and allowing completion of scatter laser photocoagulation. A large case series showed that sight threatening complications are rare and in approximately 90% of cases, vision is improved or stabilized [81]. Vitrectomy may also be beneficial for maculopathy when traction from the vitreous gel contributes to fluid accumulation.
